Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an idiopathic chronic inflammatory demyelinating disease of the central nervous system with variable extent of remyelination. Remyelination originates from oligodendrocyte (OG) precursor cells, which migrate and differentiate into mature OG. Tubulin polymerization promoting protein (TPPP/p25) is located in mature OG and aggregates in oligodendroglial cytoplasmic inclusions in multiple system atrophy. We developed a novel monoclonal anti-TPPP/p25 antibody to quantify OG in different subtypes and disease stages of MS, and possible degenerative changes in OG. We evaluated autopsy material from 25 MS cases, including acute, primary progressive, secondary progressive, relapsing remitting MS, and five controls. Demyelinated lesions revealed loss of TPPP/p25-positive OG within the plaques. In remyelination, TPPP/p25 was first expressed in OG cytoplasms and later became positive in myelin sheaths. We observed increased numbers of TPPP/p25 immunoreactive OG in the normal appearing white matter (NAWM) in MS patients. In MS cases, the cytoplasmic area of TPPP/p25 immunoreactivity in the OG was higher in the periplaque area when compared with NAWM and the plaque, and TPPP/p25 immunoreactive OG cytoplasmic area inversely correlated with the disease duration. There was a lack of phospho-TDP-43, phospho-tau, α-synuclein, and ubiquitin immunoreactivity in OG with enlarged cytoplasm. Our data suggest impaired differentiation, migration, and activation capacity of OG in later disease stages of MS. Upregulation of TPPP/p25 in the periplaque white matter OG without evidence for inclusion body formation might reflect an activation state. Distinct and increased expression of TPPP/p25 in MS renders it a potential prognostic and diagnostic marker of MS.

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

“…the oligodendroglial cytoplasm and all oligodendroglial processes [7,8], two studies previously reported that TPPP is localized in the nucleus [10,20], consistent with the present data. Höftberger and colleagues previously analyzed the localization of TPPP in the human brain by immunohistochemistry and immunoelectron microscopy, and showed that TPPP was localized in oligodendroglial nuclei as well as its cytoplasm [10].…”

“…Höftberger and colleagues previously analyzed the localization of TPPP in the human brain by immunohistochemistry and immunoelectron microscopy, and showed that TPPP was localized in oligodendroglial nuclei as well as its cytoplasm [10]. Acevedo and colleagues also found similar nuclear localization of TPPP in the non-neuronal cell lines NIH-3T3 and HeLa using immunocytochemistry [20].…”

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

“…Though the neuropathological alterations in MS are results of a complex aetiology including autoimmunity, demyelination, neuronal and axonal degeneration, the central role of oligodendrocytes has also been suggested [15], which gives our observations a wider implication. The interrelation between mitochondrial leukoencephalopathies and MS is well exemplified by the fact that the above mentioned cuprizone intoxication, presenting with a highly similar neuropathology to that observed in KSS and FL-PGC-1α-deficient mice in our study, is in fact a widely applied toxin model of MS [1,27].…”

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…distinct CNS diseases such as glioma (brain tumor) [13], multiple sclerosis (demyelination) [14,15] or synucleinopathies (pathological inclusions) [16]. In fact, TPPP/p25 is able to induce α-synuclein (SYN) aggregation [17] in vitro; however, its overexpression and co-localization with SYN in human brain is a characteristic symptom of Parkinson's disease [16], thus we have suggested TPPP/p25 as a biomarker of synucleinopathies [16].…”